Regulatory effects of IFN-β on production of osteopontin and IL-17 by CD4+ T Cells in MS

Abstract

IFN-β currently serves as one of the major treatments for MS. Its anti-inflammatory mechanism has been reported as involving a shift in cytokine balance from Th1 to Th2 in the T-cell response against elements of the myelin sheath. In addition to the Th1 and Th2 groups, two other important pro-inflammatory cytokines, IL-17 and osteopontin (OPN), are believed to play important roles in CNS inflammation in the pathogenesis of MS. In this study, we examined the potential effects of IFN-β on the regulation of OPN and IL-17 in MS patients. We found that IFN-β used in vitro at 0.5-3ng/mL significantly inhibited the production of OPN in primary T cells derived from PBMC. The inhibition of OPN was determined to occur at the CD4+ T-cell level. In addition, IFN-β inhibited the production of IL-17 and IL-21 in CD4+ T cells. It has been described that IFN-β suppresses IL-17 production through the inhibition of a monocytic cytokine, the intracellular translational isoform of OPN. Our further investigation demonstrated that IFN-β also acted directly on the CD4+ T cells to regulate OPN and IL-17 expression through the type I IFN receptor-mediated activation of STAT1 and suppression of STAT3 activity. Administration of IFN-β to EAE mice ameliorated the disease severity. Furthermore, spinal cord infiltration of OPN+ and IL-17+ cells decreased in IFN-β-treated EAE mice along with decreases in serum levels of OPN and IL-21. Importantly, decreased OPN production by IFN-β treatment contributes to the reduced migratory activity of T cells. Taken together, the results from both in vitro and in vivo experiments indicate that IFN-β treatment can down-regulate the OPN and IL-17 production in MS. This study provides new insights into the mechanism of action of IFN-β in the treatment of MS. © 2009 Wiley-VCH Verlag GmbH & Co. KGaA.